The mRNA quality-control mechanism known as nonsense mediated mRNA decay (NMD) degrades mRNAs having one or more premature stop codons within intragenic regions. Genetic mutations introducing such termination defects have been causally linked to a number of human genetic diseases, including Duchenne muscular dystrophy (caused by a premature stop codon mutation in the gene encoding dystrophin), nonsense mutation-mediated cystic fibrosis (caused by a premature stop codon mutation in the gene encoding the cystic fibrosis transmembrane conductance regulator), and numerous cancers. Of NMD-implicated cancers, the most prominent is a widespread form of breast cancer that is caused by a premature stop codon in the BRCA1 or BRCA2 tumor suppressor gene.
Previous small molecule based therapeutic efforts to inhibit termination events at premature stop codons have been limited by clinically significant side effects. Accordingly, there is a need to design and develop broadly applicable small-molecule therapeutic agents capable of specifically interfering with the recognition of premature stop codons, while leaving eRF1-catalyzed termination at naturally-occurring stop codons unperturbed. Such molecules can be used to abrogate the NMD pathway and rescue production of the protein encoded by the premature-stop codon-containing mRNA. The invention described herein addresses this need.